The steroid hormone, progesterone (P), is a central coordinator of all aspects of female reproductive activity. The effects of P are mediated by two intracellular receptors, termed PR-A and PR-B, that arise from the same gene and display both distinct and overlapping transcription regulatory when examined in cell culture systems. The overall objective of this project is to establish the selective physiological roles of the individual PR isoforms in the female reproductive tract. To this end, we have used gene targeting in embryonic stem cells to selectively ablate expression of either the PR-A (PRAKO) or PR-B (PRBKO) isoform in mice. During the previous phase of this project, we have used these models to examine the selective physiological activities of PR-A and PR-B in their natural physiological context. Our analysis to date has shown that PR-A and PR-B mediate mostly distinct but partially overlapping reproductive tissue selective physiological responses to P. As a logical continuation of this effort, the specific aims of this renewal application are as follows: 1) To elucidate the PR isoform dependent signaling pathways in ovarian granulosa cells that are required for rupture of the preovulatory follicle during ovulation and to complete analysis of the endocrine status of PRAKO and PRBKO mice. 2) To examine the isoform selective molecular mechanisms by which PR-A and PR-B differentially regulate uterine epithelial proliferation, uterine receptivity and stromal decidualization, and 3) To examine the selective contributions of the PR-A and PR-B isoforms to a) P dependent proliferation and differentiation of the normal mammary gland, b) PR dependent mammary tumorigenesis and c) hormonal protection of young animals against mammary tumorigenesis.